Wee1 opposes APC/C Cdh1 activity to promote S-phase entry
Authors:
- Luc-Alban VuillemenotLVLuc-Alban Vuillemenot
- Lucas G. MoralesLMLucas G. Morales
- Calin-Mihai DragoiCDCalin-Mihai Dragoi
- Betheney R. PennycookBPBetheney R. Pennycook
- Edward HarrisEHEdward Harris
- Liuyang C. LinLLLiuyang C. Lin
- William A. WestonWWWilliam A. Weston
- Jade-Ellen BrownJBJade-Ellen Brown
- Emma GrahamEGEmma Graham
- Ivan AndrewIAIvan Andrew
- Georgia RoumeliotiGRGeorgia Roumelioti
- Alex MontoyaAMAlex Montoya
Preprint
Abstract
Wee1 phosphorylates and inhibits CDK activity to inhibit mitotic entry and establish a G2 DNA damage checkpoint. Consequently, Wee1 inhibitors are in clinical trials, developed to be synthetically lethal in TP53 mutant tumours that become reliant on a Wee1-mediated DNA damage checkpoint. However, Wee1 inhibitors have efficacy in TP53 wild-type tumours and many trials have been terminated due to high levels of toxic side-effects, suggesting that Wee1 has unknown functions. Here, we show that Wee1 promotes cell cycle re-entry from quiescence (G0) by opposing the activity of the E3 ubiquitin ligase, APC/C Cdh 1 . Wee1 phosphorylates Cdh1 ( FZR1 ) at key residues that mediate the interaction between Cdh1 and APC/C. Cells with loss-of-function of Wee1 during G0/G1 have delayed S-phase entry, an impaired G1/S transition, abnormal S-phase accumulation of the CDK inhibitor p21 and enter a p21-dependent G2 arrest. Reduced expression of APC/C Cdh 1 or p21 renders cells more sensitive to acute Wee1 inhibition and both pathways are downregulated in acquired Wee1 inhibitor resistance. Our study reveals a new cell cycle control mechanism that has implications for how Wee1 inhibitors should be used in the clinic.Keywords
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